The present invention relates to novel compounds, pharmaceutical formulations comprising these compounds, and the use of these compounds in therapy. More particularly, the present invention relates to compounds for the prophylaxis and treatment of herpes viral infections.
Of the DNA viruses, those of the herpes group are the sources of the most common viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6), human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8). HSV-1 and HSV-2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host's neural cells; once infected, individuals are at risk of recurrent clinical manifestations of infection which can be both physically and psychologically distressing.
Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpes labialis and genital herpes. HSV infection is often characterised by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host's sight. Infection in the new-born, in immunocompromised patients or penetration of the infection into the central nervous system can prove fatal. In the U.S. alone, 40 million individuals are infected with HSV-2, a number that is expected to increase to 60 million by 2007. Over 80% of individuals infected with HSV-2 are unaware they carry and spread the virus, and of those diagnosed less than 200% received oral therapies. The net result is that less than 50% of the infected population are treated. Likewise of the 530 million individuals worldwide who carry the HSV-1 virus, 81% of the symptomatic population remain untreated. No cure exists for HSV infection, and once infected, individuals carry the virus for life in a dormant state. Reactivation of the virus from latency occurs periodically and may be triggered by stress, environmental factors, and/or suppression of the host immune system. Currently, the use of nucleoside analogs such as valaciclovir (VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managing genital herpes virus outbreaks.
Varicella Zoster Virus (VZV) (also known as herpes zoster virus) is a herpes virus which causes chickenpox and shingles. Chickenpox is the primary disease produced in a host without immunity, and in young children is usually a mild illness characterised by a vesicular rash and fever. Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV. The clinical manifestations of shingles are characterised by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges become affected. VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
In common with other herpes viruses, infection with CMV leads to a lifelong association of virus and host. Congenital infection following infection of the mother during pregnancy may give rise to clinical effects such as death or gross disease (microcephaly, hepatosplenomegaly, jaundice, mental retardation), retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients who are immunocompromised for example as a result of malignancy, treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency Virus, may give rise to retinitis, pneumonitis, gastrointestinal disorders and neurological diseases. CMV infection is also associated with cardiovascular diseases and conditions including restenosis and atherosclerosis.
The main disease caused by EBV is acute or chronic infectious mononucleosis (glandular fever). Examples of other EBV or EBV associated diseases include lymphoproliferative disease which frequently occurs in persons with congenital or acquired cellular immune deficiency, X-linked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin's lymphoma, thymomas and oral hairy leukoplakia. EBV infections have also been found in association with a variety of epithelial-cell-derived tumours of the upper and lower respiratory tracts including the lung. EBV infection has also been associated with other diseases and conditions including chronic fatigue syndrome, multiple sclerosis and Alzheimer's disease.
HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients, respectively, and may be associated with other diseases such as multiple sclerosis. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease aetiology.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is aetiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
PCT Publication No. WO 91/00092 to SmithKline Beecham Corp. refers to imidazo[1,2-a]pyridine compounds of formula (I)
wherein:W1 is —(CR4R5)—(CR6R7)—, —CR5═CR7—, —N═CR7—, —S(O)m— or —O—; one of R1 and R0 is 4-pyridyl or C1-4alkyl-4-pyridyl, provided that when R1 is C1-4alkyl-4-pyridyl the alkyl substituent is located at the 2-position of the pyridine ring, and the other of R1 and R0 is                (a) phenyl or monosubstituted phenyl wherein said substituent is C1-3alkylthio, C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52-alkenyl-1-sulfinyl, 1-acyloxy-1-alkylthio, C1-2alkoxy, halo, C1-4alkyl or Z wherein Z is —S—S—Z1 and Z1 is phenyl or C1-9alkyl; or        (b) disubstituted phenyl wherein said substituents are independently C1-3alkylthio, C1-2alkoxy, halo or C1-4alkyl; or        (c) disubstituted phenyl wherein one of said substituents is C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52alkenyl-1-sulfinyl, or 1-acyloxy-1-alkylthio and the other is C1-2alkoxy, halo or C1-4alkyl; or        (d) disubstituted phenyl wherein the substituents are the same and are C1-3alkylsulfinyl, C2-51-alkenyl-1-thio, C2-51-alkenyl-1-sulfinyl, C3-52-alkenyl-1-thio, C3-52alkenyl-1-sulfinyl, or 1-acyloxy-1-alkylthio or wherein the substituents together form a methylene dioxy group; or        (e) monosubstituted phenyl wherein said substituent is        
                t is 0 or 1; W1, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined herein;        provided that:        1) when W1 is —(CR4R5)—(CR6R7)— then                    n is 0 or 1;            and R2, R3, R4, R5, R6, R7, R8 and R9 are independently —H or C1-2alkyl; and            when R1 or R0 is 4-pyridyl, the other of R1 and R0 is other than mono-C1-2alkoxy-substituted phenyl or mono-halo-substiuted phenyl; or            when n is O, R4 and R5 together are oxo; R4 and R5 are both fluoro, or one of R4 and R5 is H and the other is OH;                        2) when W1 is —CR5═CR7— or —N═CR7— then                    n is 1;            R3, R5, R7 and R9 are independently —H or C1-2alkyl; and            R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic pyridine or pyrimidine ring;                        3) when W1 is —S(O)m— then                    m is 0, 1 or 2;            n is 1 or 2;            R3 and R9 are independently —H or C1-2alkyl;            R2 and R8 are independently —H or C1-2alkyl or R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic thiazole ring;            further provided that:            (a) when R2 and R8 are independently —H or C1-2alkyl and R1 or R0 is 4-pyridyl, then the other of R1 and R0 is other than mono-C1-2alkoxy-substituted phenyl or mono-halo-substituted phenyl; and            (b) when R2 and R8 together represent a double bond in the B ring such that the B ring is an aromatic thiazole ring, the m is 0 and n is 1; and                        4) when W1 is —O— then                    n is 1;            R3 and R9 are independently —H or C1-2alkyl; and            R2 and R8 together represent a double bond in the B ring such that the            B ring is an aromatic oxazole ring;or a pharmaceutically acceptable salt thereoffor use in the inhibition of interleukin-1 and tumor necrosis factor production by monocytes and/or macrophages.                        
PCT Publication No. WO 01/14375 to AstraZeneca AB relates to imidazo[1,2-a]pyridine and pyrazolo[2,3-a]pyridine derivatives of formula (I)
wherein Ring A is a imidazo[1,2-a]pyridine or pyrazolo[2,3-a]pyrid-3-yl; R2 is as defined therein, m is 0–5; wherein the values of R2 may be the same or different; R1 is as defined therein; n is 0 to 2, wherein the values of R1 may be the same or different; Ring B is phenyl or phenyl fused to a C5-7cycloalkyl ring; R3 is as defined therein; p is 0–4; wherein the values of R3 may be the same or different; R4 is as defined therein; q is 0–2; wherein the values of R4 may be the same or different; and whrein p+q≦5; or a pharmaceutically aceptable salt or an in vivo hydrolysable ester thereof. The use of the compounds of formula (I) in the inhibition of cell cycle kinases CDK2, CDK4 and CDK6 are also described.
PCT Publication No. Wo 96/34866 to Fujisawa Pharmaceutical Co. Ltd. relates to imidazo[1,2-a]pyridine and imidazo[1,2-a]pyridezine derivatives of formula (I)
wherein X is vinylene or a group of formula (a):                —NHCO—, —NHSO2—, —OCO—, OCH2—, —NHCOCO—, —NHCOCH═CH—,        —NHCOCH2—, —NHCONH or —N(R5)—CO—,Y is heterocyclic group which may have one or more suitable substituent(s), or aryl which may have one or more suitable substituent(s), Q is CH or N, and I is an integer of 0 or 1, which are the inhibitors of bone resorption and bone metabolism, to processes for preparation theroef, to a pharmaceutical compositon comprising the same and to a method for the treatment of disease caused by abnormal bone metabolism in human being or an animal.        
U.S. Pat. No. 5,498,774 and European Patent No. 0 404 190 to Mitsudera et al., relates to condensed heterocyclic compounds of the general formula (I):
wherein Q is a condensed heterocyclic group having a nitrogen atom in the bridgehead which is unsubstituted or substituted, X is a hydrogen atom or a group attached through C, O, S or N, and Y is an electron attractive group; or its salt which is useful as an agricultural chemical.